Farmacoterapias paliativas para la disnea de la fibrosis quística
Resumen
Antecedentes
La fibrosis quística es una enfermedad genética recesiva autosómica que limita la vida. La sensación de disnea es frecuente en la fibrosis quística, especialmente a medida que progresa la enfermedad. La reversión de la causa subyacente es la prioridad al tratar la disnea (falta de aliento), aunque cuando no es factible, la paliación (alivio) se convierte en el objetivo principal para mejorar la calidad de vida del individuo. Se han usado diversos fármacos administrados por diversas vías, aunque no hay guías definitivas disponibles. Se necesita una revisión sistemática para evaluar dichos tratamientos.
Objetivos
Evaluar la eficacia y la seguridad de los fármacos utilizados para aliviar la disnea en pacientes con fibrosis quística.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis Quística (Cochrane Cystic Fibrosis Group), compilado a partir de búsquedas en bases de datos electrónicas y búsquedas manuales en revistas y libros de resúmenes de congresos.
Fecha de la última búsqueda: 24 julio 2017.
Se hicieron búsquedas de ensayos en curso en bases de datos (clinicaltrials.gov, el ISRCTN registry, el Clinical Trials Registry India y WHO ICTRP). Estas búsquedas se hicieron por última vez 31 de julio de 2017.
Criterios de selección
Se planificó incluir ensayos controlados aleatorizados y cuasialeatorizados en pacientes con fibrosis quística (diagnosticados mediante una prueba positiva de cloruro en sudor o una prueba genética) que presentan disnea. Se consideraron los estudios que comparaban cualquier fármaco utilizado para aliviar la disnea versus otro fármaco administrado por cualquier vía (inhalado [nebulizado], intravenoso, oral, subcutáneo, transmucoso [incluido bucal, sublingual y intranasal] y transdérmico).
Obtención y análisis de los datos
Los autores evaluaron los resultados de la búsqueda de acuerdo a los criterios de inclusión predefinidos.
Resultados principales
La búsqueda produjo sólo un estudio (diseño cruzado), que no cumplió con los criterios de inclusión debido a que no había datos disponibles del primer período de tratamiento solo.
Conclusiones de los autores
Debido a la falta de evidencia disponible, esta revisión no puede proporcionar ninguna información para la práctica clínica. Los autores piden una investigación específica en este ámbito después de tener en cuenta las consideraciones éticas pertinentes. La investigación debe centrarse en la eficacia y la seguridad de los fármacos y medir la eficacia en cuanto a la mejoría en la calidad de vida, las puntuaciones de la disnea y la estancia hospitalaria.
PICOs
Resumen en términos sencillos
Farmacoterapias para aliviar la disnea en la fibrosis quística
Pregunta de la revisión
¿Cuál es la evidencia de que las farmacoterapias para la disnea (también conocida como falta de aire) en los pacientes con fibrosis quística son efectivas y seguras?
Antecedentes
La fibrosis quística es una enfermedad genética que limita la vida. A medida que progresa la enfermedad, se forma moco pegajoso y espeso en los pulmones, el páncreas y otros órganos. Este moco espeso aumenta el riesgo de infección, bloquea las vías respiratorias y causa disnea grave. El alivio de esta disnea es un objetivo importante para la atención de los pacientes con fibrosis quística. Se han sugerido muchos métodos para considerar este problema y se ha informado que muchos fármacos alivian la disnea. Los fármacos pueden ser administrados a través de diversas vías ‐ pueden ser inhalados, ingeridos, inyectados bajo la piel, en el músculo o en una vena o absorberse a través de la piel (en el cuerpo o a través de las membranas dentro de la boca o la nariz). A pesar de que hay tantos fármacos disponibles, no hay guías definidas para las farmacoterapias dirigidas a aliviar la disnea en pacientes con fibrosis quística.
Fecha de la búsqueda
La evidencia del Registro de Ensayos Cochrane de Fibrosis Quística son actuales hasta: 24 de julio de 2017; las búsquedas de registros de ensayos en curso están actualizadas hasta el 31 de julio de 2017.
Características de los estudios
Se había planificado incluir estudios que comparaban diferentes tratamientos para aliviar la disnea en pacientes con fibrosis quística en los que los participantes habían sido asignados a diferentes grupos de tratamiento al azar. La búsqueda encontró sólo un estudio en el que siete personas recibieron primero un fármaco llamado hidrocodona o un placebo (tratamiento de simulacro) y luego cambiaron al otro tratamiento; aunque este estudio no presentó los resultados por separado para cada brazo de tratamiento, de manera que no fue posible incluirlo en la revisión.
Resultados clave
Ningún estudio cumplió los criterios de inclusión, por lo tanto, no es posible formular observaciones sobre los resultados que se deseaban presentar en esta revisión. Hasta que haya evidencia disponible, los autores de la revisión opinan que es aconsejable que los médicos sigan cualquier guía local o nacional. Los autores recomiendan que la investigación en esta área debe tener en cuenta las consideraciones éticas y debe centrarse en la seguridad de los fármacos, la mejoría en la calidad de vida, las puntuaciones de la disnea y la duración de la estancia hospitalaria.
Authors' conclusions
Background
Description of the condition
Cystic fibrosis (CF) is a life‐limiting autosomal recessive genetic illness. In the past 70 years, the survival of people with CF has improved substantially due to advances in medical care, both in diagnostic techniques and in the pharmacological and non‐pharmacological treatment of the condition (Dasenbrook 2012). Before the introduction of widespread screening programmes, CF was diagnosed by the age of two years in more than 70% of individuals with the condition, but now it can be diagnosed very soon after birth (median age of four months) (CF Foundation 2013; Kleven 2008). The predicted median age of survival for a person with CF has increased progressively; in the UK it was recently reported as being 43.5 years (UK CF Trust 2014), while in the USA it was reported to be over 41 years (CF Foundation 2013). However, according to the WHO, globally the median survival is 33.5 years (WHO 2015). Dodge reported that median survival will be over 50 years of age for those born after 2000 (Dodge 2007). More than 49% of people with CF are aged 18 years or older (CF Foundation 2013) and the UK CF Registry states that more than 58% of people with CF are over 16 years of age (UK CF Trust 2014). The global incidence of CF is varied. It is severely under‐diagnosed in Asia, while in the European Union it is estimated at 1 in 2000 to 3000 births and in the USA it is estimated as 1 in 3500 births (WHO 2015). Approximately 1000 new cases of CF are diagnosed each year in the USA (CF Foundation 2010b; O'Sullivan 2009).
The abnormal CF gene and its mutated protein lead to thick and sticky mucus in the airways (Torphy 2009). An absence of the cystic fibrosis transmembrane regulator (CFTR) at the surface of airway epithelium decreases chloride secretion and increases sodium absorption, leading to water depletion from the airway surface; this results in impaired mucociliary clearance which favours infections, due to bacterial colonisations like Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, etc. (Gautam 2015), and inflammation, thereby causing lung destruction (Dasenbrook 2012). In people with CF, thick, sticky mucus forms in the lungs, pancreas, and other organs. In the lungs, this mucus blocks the airways, making it hard to breathe and leading to serious lung infections and lung damage (CF Foundation 2010a). The natural history of CF is a progressive decline in lung function secondary to chronic airway infection. Respiratory failure is the most common cause of death. In addition to nausea, pain and anxiety, breathlessness (also known as dyspnoea) is a distressing symptom requiring medical management, especially in the terminal phase of CF (Sands 2011). Contemporary theories suggest that breathlessness radiates from multiple sensory inputs in the brain, and evokes a response i.e. sending motor signals or nerve impulses to both the breathing muscles and to the sensory cortex (corollary discharge) (Killian 2005; Peters 2006). The release of these signals or impulses from the respiratory centres in the brainstem represents a complex processing and integration of multiple inputs, which include receiving information regarding central and peripheral chemoreceptor stimulation, forced displacement in the chest wall, lung stretch and information from higher levels in the brain (Killian 2005).
A feeling of shortness of breath is common in people with CF and palliation (easing) becomes the primary goal as the disease progresses. In the later stages of the disease, people with CF also experience increased respiratory exacerbations and oxygen dependence.
Description of the intervention
The easing of breathlessness is a reasonable goal to improve comfort as the disease progresses. Severe breathlessness is one of the most troubling aspects of CF for many clinicians and patients (Robinson 2000). A range of drugs administered by various routes have been used, but no definite guidelines are available. Drugs such as morphine and fentanyl have been tried and proved useful in relieving breathlessness (Booth 2009; Cohen 2002; Graff 2004; Janahi 2000; Kallet 2007), in addition to their use in palliative sedation (Palliative Sedation Protocol 2004; Sands 2011). Intravenous morphine of less than 5 mg/hour has been shown to be sufficient in relieving breathlessness in over 50% of people with CF (Robinson 2000). Anxiolytic agents depress the hypoxic or hypercapnic ventilatory responses and thus relieve breathlessness, but also alter emotional responses related to breathlessness. Other drugs classified as mucolytics (e.g. dornase alfa and nebulised hypertonic saline), inhaled anaesthetics (e.g. lidocaine), inhaled beta‐2 adrenergic agonists and inhaled anti‐cholinergics have also been used for easing breathlessness in CF (ATS 1999; Parshall 2012).
How the intervention might work
Drug treatments for easing breathlessness can be inhaled or administered through intranasal, oral, subcutaneous, transdermal, buccal, intravenous or intra‐muscular routes (Simon 2012).
Opiates and inhaled anaesthetic agents decrease the perceptual responses and thus lessen the intensity of respiratory sensation (Hayes 2010; Jennings 2002). The exact mechanism by which opioids alleviate breathlessness is still not known. However, suggested mechanisms of action include reducing the effects of arterial carbon dioxide (pCO₂) levels and oxygen (pO₂) levels on ventilation, reducing oxygen consumption as well as altering the individual's perception of breathlessness (ATS 1999; Pattinson 2009).
In contrast, anxiolytic agents depress the hypoxic or hypercapnic ventilatory responses and thus relieve breathlessness, but also alter emotional responses related to breathlessness (Tait 2014). These drugs include clonazepam, which has a long half‐life allowing administration as a subcutaneous bolus once or twice a day and midazolam which has a short half‐life and therefore requires a syringe driver or frequent subcutaneous administration to provide the equivalent outcome. Both sublingual and subcutaneous clonazepam have a quick onset of action, making clonazepam suitable for breakthrough symptoms (Tait 2014).
Mucolytics like dornase alfa and N‐acetyl cysteine act by either reducing the viscosity or adhesive properties of the mucus, which helps in easing the breathlessness (Henke 2007). Inhaled hypertonic saline acts by hydrating the thick mucus present and helps to re‐establish the deficient aqueous surface layer which is absent in people with CF (Donaldson 2006). The inhaled anticholinergic agents when administered induce bronchodilation and relieve breathlessness (Weinberger 2002).
Why it is important to do this review
A comparison of the various drug treatments may help in finding better options for the amelioration of the symptoms of breathlessness in people with CF. As there are no defined guidelines for the palliation or easing of breathlessness in CF or the evaluation of such treatments, a systematic review is required to identify the best drug treatment.
Objectives
To assess the efficacy and safety of drugs used to ease breathlessness in people with CF.
Methods
Criteria for considering studies for this review
Types of studies
In this systematic review, it was planned to include randomised controlled trials (RCTs) and quasi‐RCTs. We had also planned only to include cross‐over studies, if first‐arm data were available.
Types of participants
People with CF (diagnosed by a positive sweat chloride test or genetic testing) of either sex, of any age group and experiencing breathlessness.
Types of interventions
Comparisons of pharmacological interventions for dyspnoea in CF were eligible for inclusion. We planned to compare different drug classes used to treat breathlessness in CF.
In a post hoc change, while extending the review from end‐stage to any stage, we decided to also include studies of pharmacological interventions compared with placebo.
Types of outcome measures
Primary outcomes
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Breathlessness (dyspnoea) score (for severity of breathlessness) as measured by a validated scoring system, e.g. modified Borg score (Hommerding 2010), a visual analogue scale (VAS) (Gift 1989), numerical rating scales (NRS), the Chronic Respiratory Disease Questionare (CRQ), Medical Research Council Scale (MRC) (Bausewein 2008)
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Number of episodes of breathlessness
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Time to next episode of breathlessness
Secondary outcomes
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Quality of life (QoL) (measured by a validated scoring system e.g. Cystic Fibrosis Questionnaire‐Revised (CFQ‐R) (Quittner 2009))
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Need for change of therapy or addition of therapy
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Hospitalization
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number of visits to emergency department
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duration of hospital stay
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Adverse events (e.g. diarrhoea, headache, vomiting, etc.)
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mild
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severe (e.g. hospitalizations due to adverse drug reaction or stopping of a particular drug due to adverse reaction)
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Blood oxygen saturation (SpO₂) levels measured as a continuous variable
Search methods for identification of studies
We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.
Electronic searches
We searched for relevant studies from the Group's Cystic Fibrosis Trials Register using the term: dyspnea.
The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cochrane Cystic Fibrosis and Genetic Disorders Group website.
Date of most recent search: 24 July 2017.
We also searched for ongoing trials in the following databases using the terms 'cystic fibrosis' AND 'dyspnoea' AND 'pharmacotherapy' for all years:
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Clinical Trials Registry India (CTRI) (ctri.nic.in/Clinicaltrials/login.php);
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clinicaltrials.gov (clinicaltrials.gov);
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the International Standard Randomized Controlled Trial Number (ISRCTN) registry (www.isrctn.org/);
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WHO ICTRP (apps.who.int/trialsearch/).
Date of the most recent search: 31 July 2017.
Searching other resources
We had also planned to search the reference lists of the retrieved studies to identify other potentially eligible studies.
Data collection and analysis
Selection of studies
Two authors independently reviewed the abstract of the only study identified by the literature searches. If more studies had been identified, two authors would have separated them as excluded or not excluded following the initial review of title and abstract. Two authors would then have independently screened the full texts (if available) of the studies labelled as not excluded against the inclusion criteria and finally decided on the inclusion of the studies as per theCochrane Handbook of Systematic Reviews of Interventions (Higgins 2011a). The authors would have resolved discrepancies by discussion with the arbiter (MS).
Data extraction and management
If any studies are included in future updates, the authors will independently extract the data from the included studies on separate study report forms. They will resolve any disagreements through discussion. If needed, they will request further information from the study authors (Higgins 2011b). Authors will then enter the extracted data into Review Manager (RevMan) software for analysis (Review Manager 2014)
Assessment of risk of bias in included studies
If any studies are included in future updates, the review authors will assess these for risks of bias using the Cochrane risk of bias tool (Higgins 2011c). The tool assesses the biases introduced through inadequacies in random sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessments, reporting of incomplete outcome data and selective reporting. The review authors will judge each of these criteria to have a low, unclear or high risk of bias. The risk of bias assessment will follow the same process as data extraction.
Measures of treatment effect
If, in future, the review authors are able to report results for dichotomous outcomes (adverse events, the need for change of therapy, increased tolerance to activities), they will use the risk ratios (RR) with 95% confidence intervals (CIs) as the effect measure. For continuous outcome data (breathlessness score, duration of period free from breathlessness, QoL scores, number of visits to emergency department, duration of hospital stay, SpO₂ levels), they will calculate the mean difference (MD) with 95% CIs in accordance with theCochrane Handbook of Systematic Reviews of Intervention (Deeks 2011). The authors only plan to pool the QoL results using the MD with 95% CIs if a standardized scale or the same scale is used across the studies. If this is not the case, they will use the standardized mean difference (SMD) with 95% CIs (Deeks 2011). The authors plan to analyse data for the frequency of attacks and the number of admissions as dichotomous data and report the rate ratios using the generic inverse variance method as described in theCochrane Handbook of Systematic Reviews of Interventions (Deeks 2011; Higgins 2011a; Higgins 2011b). The authors plan to present data at the final time point reported in the studies (for cross‐over studies, they will present data from the first arm only).
Unit of analysis issues
For any cross‐over studies included in future updates of this review, the authors will use only first‐arm data as participants may not recover to baseline and, in addition to introducing a unit of analysis error, multiple treatment episodes may not be comparable (Elbourne 2002).
Dealing with missing data
If there appear to be any data missing from studies the authors include in future updates of the review, they will contact the study authors for these. If this is not possible, for continuous variables where standard deviations (SDs) are not published, the authors will impute the missing SD using a correlation co‐efficient (Higgins 2011d). Where possible, the authors will perform intention‐to‐treat analyses.
Assessment of heterogeneity
If the authors include studies in future updates of the review, they will assess the forest plot visually for heterogeneity. They will also compute the statistical heterogeneity in the included studies using the Chi² test (considered significant when corresponding P ≤ 0.10) with which a calculation of I² statistic is planned (Higgins 2003). The authors will interpret this value based on thresholds as identified in theCochrane Handbook for Systematic Reviews of Interventions (Deeks 2011):
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0% to 40% as probably not important;
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30% to 60% as moderate heterogeneity;
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50% to 90% as substantial heterogeneity; and
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75% to 100% as considerable heterogeneity.
Assessment of reporting biases
The review authors will contact the authors of any studies included in future updates of the review in an attempt to identify unpublished studies. They also plan to contact the authors of any potentially relevant studies published only in abstract form for additional data. The authors will attempt to identify evidence of outcome reporting biases by comparing the published reports to the study protocols, if these are available. If protocols are not available, the review authors will compare the 'Methods' section to the 'Results' section of the published paper to identify any outcomes that were measured but not reported. If they include and combine sufficient studies (n = 10), they will make further attempts to identify reporting biases by constructing and inspecting funnel plots; they will interpret these in the context of study sizes and methodological rigour (Sterne 2011).
Data synthesis
If the authors include studies in future updates of the review, they will pool the outcome measures using a fixed‐effect method for meta‐analysis. However, if they identify at least substantial heterogeneity, as defined above, they will use the random‐effects method for meta‐analysis.
Subgroup analysis and investigation of heterogeneity
If, in future, the authors are able to combine data from two or more studies and find moderate to considerable heterogeneity between the studies (as defined by I² ranges above (Assessment of heterogeneity)), they will undertake subgroup analyses based on age (less than 18 years versus 18 years and above) and according to the drug used, e.g. nebulized morphine or nebulized dornase alfa. If they find a sufficient number of studies for any given drug (i.e. two or more), they will consider a dose‐specific subgroup analysis.
Sensitivity analysis
If, in the future, the authors are able to combine data from a sufficient number of studies, they will investigate the effect of decisions about missing data and risk of bias judgements made by the review team by undertaking sensitivity analyses of the affected components. If they manage missing data by imputing values, they will investigate the effect of these manipulations by repeating the analyses without these imputations. If they include studies with a high risk of bias in the analysis, they will repeat the analysis using only studies with a low risk of bias.
Results
Description of studies
The searches found only one study which was excluded as it did not fit the inclusion criteria for the review (Figure 1).
Study flow diagram.
Included studies
No studies were included in the review.
Excluded studies
Only one study was found after searching various databases (Browning 1988). This study was only available as an abstract and was excluded since it was a cross‐over study that did not present separate first‐arm data.
Please also refer to the table 'Characteristics of excluded studies'.
Risk of bias in included studies
There were no studies included in the review.
Effects of interventions
There were no studies included in the review.
Discussion
Summary of main results
There were no randomised controlled trials (RCTs) identified which fulfilled the review's inclusion criteria. The only study found in the searches compared the effect of an active intervention (hydrocodone) to placebo for dyspnoea in adults with cystic fibrosis (CF). The study was cross‐over in design, but did not report data separately for the different treatment arms.
Agreements and disagreements with other studies or reviews
The review found that there is lack of studies discussing palliative drug treatments for breathlessness in people with CF. The available literature is in the form of case studies, which need to be assessed when making clinical decisions (Cohen 2002; Graff 2004; Hayes 2010; Janahi 2000). The excluded study was cross‐over in design and compared hydrocodone to placebo (Browning 1988). Results reported at the end of the study showed improvement improvement in exercise performance with hydrocodone, although the sample size was very small. Recent studies have stressed the importance of advance care planning (ACP) (Dellon 2016; Madge 2016). Palliative treatment for breathlessness is therefore more important as it is a part of ACP. There is a need for better palliative care training and education to health professionals involved in caring for people with CF (Goggin 2016; Linnemann 2015). As ACP involves a discussion of various available treatment options, it is very important to have comparative information regarding the drug therapies for breathlessness.
A recently published letter concluded that opioids help in improving treatment of breathlessness (Ekstorm 2017). There are also two other Cochrane Reviews which compare systemic opioids to placebo for treating chronic breathlessness and have shown benefits for relieving breathlessness with low quality evidence (Barnes 2016; Ekstorm 2015). One of these reviews compared systemic opioids to placebo in any advanced disease and in adults with terminal illnesses (Barnes 2016), while the second review discussed the same comparison specifically in people with chronic obstructive pulmonary disease (COPD) (Ekstorm 2015). This Cochrane Review aims to compare not just systemic opioids, but all possible pharmacotherapies that may be used to relieve breathlessness in people with CF.
